论文总字数：17942字

摘 要

疟疾是一种古老的疾病，由疟原虫感染而引起。全球有107个国家和地区的32亿人口，特别是在南美洲、非洲、南亚和旧中国，都遭受到疟疾的威胁，严重危害人民生活质量和影响社会经济发展。由于抗疟药物的广泛使用，恶性疟原虫几乎对现有用于临床的各类抗疟药物都产生了不同程度的抗性，目前迫切需要针对寄生虫生命周期多个阶段，设计一系列新型抗疟药物来解决目前药物产生的耐药性问题。近年来，疟原虫二氢叶酸还原酶（DHFR）是诸如乙胺嘧啶和环胍之类的抗叶酸抗疟药物的作用靶标，其临床功效已经由于酶多个位点的突变引起的抗性而受到损害。在这里，我们通过合成一系列噻吩并嘧啶类化合物，并对其抗疟活性（包括抗恶性疟）进行研究，旨在寻找一类活性高、生物利用度高及低毒性的新型抗疟化合物，为今后的新药研发奠定基础。此嘧啶类化合物大都作用于疟原虫的二氢叶酸还原酶，实现对该酶催化还原活性的抑制，从而阻断了疟原虫四氢叶酸的合成途径，阻碍叶酸代谢并由此发挥着抗疟活性。

本实验为两步反应，第一步利用2,4-二氯噻吩并［3,2-d］嘧啶为原料和环己胺反应，原料2位氯原子被环几胺取代，合成2-氯-4-环几胺基噻吩并［3,2-d］嘧啶，再将在用多种取代伯胺对一步合成产物4位氯原子进行取代，生成相应的多种取代的噻吩并嘧啶骨架化合物。此法合成和纯化的操作较简便，适应性广泛，本文利用气质谱图将合成的有机化合物进行定性和定量的分析，并通过核磁氢谱和碳谱对所合成的噻吩并嘧啶类化合物进行表征。

关键词： 疟疾 抗疟药 噻吩并嘧啶 药物合成

Abstract

Malarial is an ancient and life-threating disease caused by infection with protozoan parasites of the genus plasmodium, especially in South America, Africa, South Asia, and Old China. The 3.2 billion people in 107 countries and regions worldwide are affected by malaria seriously endangering people’s health and social economic development. With the widespread use of antimalarials, plasmodium falciparum has developed resistance to almost all types of anti-malaria drugs currently available. Therefore, novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Malarial dihydrofolate reductase(DHFR) is the target of anti-folate antimalarial drugs such as pyrimethamine and cycloguanil,the clinicial efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we propose to synthesize a series of thiazolopyrimidines and study their antimalarial activity (including falciparum malaria) in order to search for a new class of antimalarial compounds with high activity, high bioavailability and low toxicity. The compounds we attempt to synthesize are target on the malarial dihydrofolate reductase (DHFR), inhibiting the catalytic reduction activity of the enzyme and affecting folate metabolism, in order to play the role of antimalarial activity.

This experiment is a two-step reaction. We choose thiophene[3,2-d]pyrimidine as the chemical scaffold and then replace 2-chlorine with cyclohexylamine.The second step is to replace 4-chlorine with a variety kinds of primary amines.Compared to the classic compositing methods, its main virtue is that its separation and purification is much easier. The structure of the compounds we synthesized are identified by ¹H-NMR and ¹³C-NMR. GC-MS is used to analyze the qualitative and quantitative of the synthetic products.

Key words: malarial；dihydrofolate reductase；thiazolopyrimidine；pharmaceutical synthesis

目录

摘要 l

Abstract ll

第一章 前 言 1

1.1 疟疾与抗疟药 1

1.2二氢叶酸还原酶抑制剂的研究进展 2

1.3 噻吩并嘧啶骨架化合物 4

1.4 本论文的研究意义及内容 5

1.4.1 本课题研究意义 5

1.4.2 实验设计 5

第二章 实 验 7

2.1实验材料 7

2.2 实验方法 8

2.3 实验结果与讨论 11

第三章 结语与展望 20

3.1本文结语 20

3.2 工作展望 20

参考文献 21

致 谢 23

第一章 前言

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